Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0042755 (masculinization)
 2,562 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Male pseudohermaphroditism due to steroid 5 alpha-reductase deficiency is the consequence of mutations in the gene encoding the type 2 isoenzyme. Most (60%) affected subjects have homozygous mutations, and the remainder are compound heterozygotes or presumed compound heterozygotes. We report an Italian subject with phenotypic and endocrine features of 5 alpha-reductase 2 deficiency who is homozygous for a substitution mutation (H231R). Although close consanguinity is not present, genealogical data demonstrated that the parents are distantly related, and both parents and the maternal grandmother are heterozygous carriers of the mutation. The fact that this particular mutation results in the formation of an enzyme with considerable residual activity may explain in part the significant degree of virilization that took place in this subject in early infancy. This same mutation (H231R) is present in heterozygous form in two other families, an African-American family and an American family of northern European descent.
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PMID:Steroid 5 alpha-reductase 2 deficiency: virilization in early infancy may be due to partial function of mutant enzyme. 870 17

Two steroid 5 alpha-reductase isozymes designated type 1 and 2 synthesize 5 alpha-reduced androgens and other 5 alpha-reduced steroid hormones. Naturally occurring mutations in the gene encoding 5 alpha-reductase type 2 cause male pseudohermaphroditism, indicating that this isozyme is responsible for the synthesis of dihydrotestosterone required for virilization of the embryonic male urogenital tract. To determine the physiological role of 5 alpha-reductase type 1, homologous recombination in mouse embryonic stem cells was used to produce male and female mice with a disruption (null allele) in the type 1 gene (Srd5a1). Male mice lacking 5 alpha-reductase type 1 appear normal. Females exhibit a parturition defect that is maternal in origin. The parturition defect is reversed by administration of 5 alpha-androstan-3 alpha, 17 beta-diol (3 alpha-Adiol), a 5 alpha-reduced androgen previously thought to be a breakdown product. Enzymes that synthesize 3 alpha-Adiol, including 5 alpha-reductase type 1 and 3 alpha-hydroxysteroid dehydrogenase, are induced in wild type uterus during late gestation. Induction leads to peak circulating levels of 3 alpha-Adiol on days 17/18 of gestation in wild type but not mutant mice. The results document a role for 5 alpha-reduced androgens synthesized by the type 1 isozyme in normal female physiology, and they suggest that 3 alpha-Adiol is a new hormone required for parturition in mice.
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PMID:5 alpha-reduced androgens play a key role in murine parturition. 872 83

Conversion of testosterone (T) to dihydrotestosterone (DHT) in genital tissue is catalysed by the enzyme 5 alpha-reductase 2, which is encoded by the SRD5A2 gene. The potent androgen DHT is required for full masculinization of the external genitalia. Mutations of the SRD5A2 gene inhibit enzyme activity, diminish DHT formation, and hence cause masculinization defects of varying degree. The classical syndrome, formerly described as pseudovaginal perineoscrotal hypospadias, is characterized by a predominantly female phenotype at birth and significant virilization without gynecomastia at puberty. We investigated nine patients with steroid 5 alpha-reductase 2 deficiency (SRD). Phenotypes, which were classified according to the severity of the masculinization defect, varied between completely female (SRD type 5), predominantly female (SRD type 4), ambiguous (SRD type 3), predominantly male with micropenis and hypospadias (SRD type 2), and completely male without overt signs of undermasculinization (SRD type 1). T/DHT-ratios were highly increased ( > 50) in the classical syndrome (SRD type 5), but variable in the less severe affected patients (SRD types 1-4) (14-35). Mutations in the SRD5A2 gene had been characterized using PCR-SSCP analysis and direct DNA sequencing. A small deletion was encountered in two patients, while all other patients had single base mutations which result in amino acid substitutions. We conclude that phenotypes may vary widely in patients with SRD5A2 gene mutations spanning the whole range from completely female to normal male without distinctive clinical signs of the disease. Hence, steroid 5 alpha-reductase deficiency should be considered not only in sex reversed patients with female or ambiguous phenotypes, but also in those with mild symptoms of undermasculinization as encountered in patients with hypospadias and/or micropenis. A classification based on the severity of the masculinization defect may be used for correlation of phenotypes with enzyme activities and genotypes, and for comparisons of phenotypes between different patients as the basis for clinical decisions to be made in patients with pseudohermaphroditism due to steroid 5 alpha-reductase 2 deficiency.
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PMID:Phenotypic classification of male pseudohermaphroditism due to steroid 5 alpha-reductase 2 deficiency. 872 14

Androgen resistance in genetic males occurs when gonadotropins and testosterone are normal, but the physiological androgen response in androgen target organs is absent or decreased. In androgen-dependent target tissues two main defects may be found: 1) defective testosterone metabolism (5 alpha-reductase type 2 deficiency) and 2) anomalies in androgen receptors (androgen insensitivity syndrome (AIS)). The clinical manifestations of these defects vary from subjects with female external genitalia to subjects with mild forms of impaired masculinization. In particular, in the complete form of AIS (CAIS) the phenotype is feminine, and in the partial form (PAIS) the external genitalia are ambiguous with an extremely variable phenotype. The diagnosis requires clinical, hormonal, genetic, and molecular investigation for appropriate gender assignation and treatment. In AIS, cloning of androgen receptor cDNA using the polymerase chain reaction, denaturing gradient gel electrophoresis, and nucleotide sequencing have enabled a variety of molecular defects in the androgen receptor to be identified. The complexity of phenotypic presentation of AIS probably reflects the heterogeneity of androgen receptor gene mutations, but to date a relationship between genotype/phenotype has been difficult to establish, with the same point mutation reported to be associated with different phenotypic expressions. Other factors must therefore also contribute to the clinical presentation of AIS, although none have yet been identified. Establishing the functional consequences of androgen receptor mutations in vitro systems and correlating them with clinical presentation may ultimately provide an explanation for the variable clinical presentation of AIS and perhaps enable prediction of the response to androgen therapy in infants with PAIS.
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PMID:A clinician looks at androgen resistance. 873 2

5 alpha-Reductase deficiency is a rare autosomal recessive disorder of defective virilization in karyotypic males due to reduced conversion of testosterone to dihydrotestosterone. The gene encoding the affected 5 alpha-reductase type 2 enzyme has recently been cloned, and mutations within the coding region have been discovered as the cause of this disease. We address the possibility of a rapid nonradioactive molecular genetic screening technique for initial diagnosis and report different point mutations in this gene in eight unrelated patients with clinical features of 5 alpha-reductase deficiency. For molecular genetic analysis, DNA from peripheral blood leukocytes was studied. The coding region of the 5 alpha-reductase type 2 gene was characterized by exon-specific PCR amplification, nonradioactive single strand conformation analysis, and direct sequencing. In seven patients, homozygous point mutations were identified (Leu55-Gln, delta Met157, Gly196-Ser, Arg227-Gln, Ala228-Thr, and His231-Arg). One individual was a compound heterozygote carrier of two mutations (Ile112-Asn and Gln126-Arg). We conclude that molecular genetic characterization of point mutations in the 5 alpha-reductase type 2 gene may be used as an additional valuable procedure for the diagnosis of this disorder.
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PMID:Nonisotopic single strand conformation analysis of the 5 alpha-reductase type 2 gene for the diagnosis of 5 alpha-reductase deficiency. 878 7

We describe a 4 year-old male with significant virilization, but no source of endogenous or exogenous androgen excess after extensive testing. Evaluation of androgen receptor function, 5 alpha-reductase activity, steroid hormone secretion patterns, and androgen metabolite concentrations were also within the normal range. Over a 10 month period there was spontaneous resolution of the physical and behavioral signs of androgenization. We postulate a self-limited process of androgen production which may represent a yet undefined pattern of sexual precocity in males.
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PMID:Apparent self-limited androgen excess in a 4 year-old male. 888 44

A female infant with partial androgen insensitivity (PAIS) was first seen at 4 months of age with slight virilization of the genitalia and externally palpable testes. Sex chromosome was 46,XY. She received left orchidectomy and exploratory laparotomy at 2 yr of age. At exploratory laparotomy, neither a uterus nor fallopian tubes were found. The right testis was preserved by fixing it at the external inguinal ring expecting spontaneous pubertal maturation. After discharge, serum levels of LH, FSH, testosterone (T) and estradiol (E2) were measured annually, and the steroid responses to hCG stimulation were examined every two yr. At the age of 10 yr, she developed breasts and a very feminine body habitus. At 12 yr, she received a clitoroplasty and right orchidectomy. The fibroblast cultures were made from the genital skin whereby androgen receptor (AR) binding was assessed by radioreceptor assay using 3H-DHT as the ligand, and thermoinstability of AR was noted despite normal maximum binding (Bmax) and dissociation constant (Kd) at 22 degrees C. But another binding experiment with 3H-Mibolerone resulted in the lack of receptor binding. AR gene analysis with direct sequencing of coding exons of the gene revealed no abnormality of the AR gene. 5 alpha-reductase activity was normal. Aromatase activity appeared to be enhanced in the genital skin fibroblast (GSF) cells as well as in the testicular tissue. The results of these studies indicated that the patient had PAIS with impaired AR functions and increased aromatase activity. After the discharge, the patient has maintained feminine phenotype, receiving estrogen therapy with mestranol 0.02 mg/day po.
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PMID:Incomplete testicular feminization syndrome: studies on androgen receptor(AR) function, AR gene analysis, and aromatase activities at puberty and long-term observations of clinical and hormonal features from infancy to puberty. 898 Aug 96

This study examines the role of dihydrotestosterone in virilization of the developing male tammar. The onset of prostate differentiation in this marsupial species normally occurs around 25 days postpartum, long after the onset of testicular testosterone production immediately after birth and the appearance of 5 alpha-reductase in the urogenital sinus before day 10. Males treated with the 5 alpha-reductase inhibitor Finasteride had reduced prostatic growth and development, and their testicular structure was disorganized. Exogenous testosterone in males enhanced the development of prostatic buds but also caused damage to the testis structure. Treatment of female tammars with testosterone between days 20-30 postpartum stimulated prostatic tissue formation and Wolffian duct development, confirming that prostatic differentiation is initiated by androgens and occurs over a relatively narrow window of time. Testosterone had a deleterious effect on the ovary, destroying the germ cells. Although treatment with testosterone damaged gonadal cellular structure in both male and female tammar young, dihydrotestosterone is apparently necessary for stability of the seminiferous tubules in the testis. Taken together, these results suggest that dihydrotostesterone initiates prostatic development between days 20 and 25 after birth in this marsupial.
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PMID:Effects of a 5 alpha-reductase inhibitor, finasteride, on the developing prostate and testis of a marsupial. 915 6

Male pseudohermaphroditism due to 17 beta-hydroxysteroid dehydrogenase-3 (17 beta-HSD-3) deficiency and 5 alpha-reductase-2 (5 alpha-RD-2) deficiency provides natural human genetic models to elucidate androgen actions. To date, five 17 beta-HSD isozymes have been cloned that catalyse the oxidoreduction of androstenedione and testosterone and dihydrotestosterone (DHT), oestrone and oestradiol. Mutations in the isozyme 17 beta-HSD-3 gene are responsible for male pseudohermaphroditism due to 17 beta-HSD deficiency. The type 3 isozyme preferentially catalyses the reduction of androstenedione to testosterone and is primarily expressed in the testes. Fourteen mutations in the 17 beta-HSD-3 gene have been identified from different ethnic groups. Affected males with the 17 beta-HSD-3 gene defect have normal wolffian structures but ambiguous external genitalia at birth. Many are raised as girls but virilize at the time of puberty and adopt a male gender role. Some develop gynaecomastia at puberty, which appears to be related to the testosterone/oestradiol ratio. Two 5 alpha-reductase (5 alpha-RD) isozymes, types 1 and 2, have been identified, which convert testosterone to the more potent androgen DHT. Mutations in the 5 alpha-RD-2 gene cause male pseudohermaphroditism, and 31 mutations in the 5 alpha-RD-2 gene have been reported from various ethnic groups. Such individuals also have normal wolffian structure but ambiguous external genitalia at birth and are raised as girls. Virilization occurs at puberty, often with a gender role change. The prostate remains infantile and facial hair is decreased. Balding has not been reported.
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PMID:Natural potent androgens: lessons from human genetic models. 989 63

The multi-factorial etiology of hypospadias is becoming more defined with ongoing investigation. Implicated factors include testosterone biosynthesis defects, 5 alpha-reductase type 2 mutations, androgen receptor mutations (rare), IVF (progesterone administration or endocrine abnormalities associated with infertility), and environmental agents that can disrupt the male sex hormone axis. It also seems that the incidence of hypospadias is on the rise, both in the United States and in Europe. Hypospadias is a physical manifestation that may be a consequence of numerous physiological aberrations, and our ability to understand and to potentially prevent this problem will require a significant amount of additional work. Our challenge for the future remains to identify the various etiologies, provide prenatal counseling for affected families with a history of hypospadias, and minimize or eliminate exposure to environmental agents that may contribute to this problem. It is even possible that some day we may be able to offer prenatal therapy to prevent hypospadias when the risk for this birth defect seems high. Does this sound far-fetched? Consider the modern management of a family with a child born with the adrenogenital syndrome, another endocrine derangement that can cause abnormal genital development. In this situation, dexamethasone can be administered to the mother in subsequent pregnancies to prevent fetal virilization until the sex of the fetus can be determined or adrenal enzyme mutations can be excluded. Perhaps in the future a similar approach will be taken for those families with strong risk factors for hypospadias.
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PMID:What is the etiology of hypospadias? A review of recent research. 1098 77


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